IMPROVING ONCOLYTIC VESICULAR STOMATITIS VIRUS THROUGH MODULATION OF THE ANTI-TUMOUR IMMUNE RESPONSE

Abstract

<p>Despite improvements in detection and treatment, cancer is the leading cause of death worldwide. Current treatment modalities have not been able to improve the mortality rates and significant toxicities limit efficacy. Therefore there is a need for development of novel therapeutics.</p> <p>Oncolytic viruses have the ability to efficiently replicate in and destroy tumours while leaving normal tissues unharmed. These treatment platforms have been gaining momentum in recent years due to pre-clinical and clinical successes. Oncolytic viruses are extremely safe with limited toxicity observed in phase I/II clinical trials, and objective responses have been observed in some patients treated with oncolytic viruses. However, there is still room to improve on these therapeutic platforms.</p> <p>Recently, the importance of the induction of anti-tumour immunity during oncolytic virotherapy has been realized and harnessing this immune response can be used to improve current oncolytic virus platforms. To this end we have conducted numerous studies assessing our ability to improve oncolytic VSV through the addition of transgenes to enhance the immunostimulatory properties of oncolytic VSV treatment. These studies showed that only the addition of a highly secreted form of human IL-15 was able to improve VSV therapy through enhanced anti-tumour immunity. However, expressing cell-autonomous transgenes from oncolytic VSV was unable to modify the therapeutic efficacy of VSV due to limited replication, both temporally and geographically within the tumour, and the indirect vascular shutdown induced by VSV infection of tumours. We believe that the drastic vascular shutdown observed following VSV therapy is an important component to the success of VSV and we have investigated which steps in this process are critical for induction of anti-tumour immunity.</p> <p>The research presented in this thesis further enforces the requirement for induction of anti-tumour immune responses in the success of OV therapy. Our findings also indicate that manipulating the tumour as a whole, rather than the virus, will lead to improved oncolytic therapeutics.</p>